Esterodiol is a naturally occurring steroidal sex hormone known as 17 beta-estradiol or 1,3,5(10)estratriene-3,17 beta-estradiol. It has the chemical formula: ##STR1##
Progesterone is naturally occurring steroidal sex hormone also known as pregn-4-ene-3,20 dione. It has the chemical formula: ##STR2##
Estradiol is the predominant estrogen hormone produced by the human ovaries during the first half or follicular phase of the menstral cycle. Estradiol is also the principal hormone which maintains bone density, reduces vasomotor symptoms, and maintains the normal structure of the female genital organs following menopause.
Progesterone is the principal hormone of the second half, or luteal phase of the menstral cycle. Among other functions, progesterone acts as an estrogen antagonist. For example, it is well known that prolonged administration of estrogen can result in endometrial hypoplasia and even uterine cancer, whereas progesterone appears to block this unwanted effect of the endometrium.
It is desirable to use estrodiol and/or progresterone to treat a variety of endocrinol disorders, and also for use as a contraceptive. However, it is well known that neither of these compounds are suitable for oral administration due to the manner in which they are absorbed from the digestive system. In particular, these steroidal hormones are carried by the portal system to the liver, where they are rapidly metabolized into inactive metabolites. Consequently, effective oral administration has required excessively high dosage levels to compensate for the metabolic breakdown of these compounds.
In the past, different approaches have been developed to avoid these problems. One approach involves the development of numerous steroidal derivatives which can be orally administered without the objectionable metabolic destruction, and thus they can be orally administered at relatively low dosage levels. For example, estrogenic compounds such as 17 alpha-ethynyl estradiol has been developed for enhanced oral activity. Likewise, progesterone derivatives such as megastrol acetate (6-methyl-17 beta-acetoxy-4,6-pregnadiene-3,20-dione), norethindrone (17 alpha-ethynyl-17-hydroxy-4-estren-3-one), norethynodrel and norethindrone have been prepared to enhance their oral activity. Various estrodiol and progesterone derivatives having enhanced oral activity are disclosed in U.S. Pat. Nos. 3,836,651; 3,755,575, and 3,568,828.
While chemical modifications have resulted in enhanced oral activity of these steroidal hormones, they have also resulted in undesirable side effects. In particular, the synthetic progestins are well known for their side effects, which include masculinization and adverse effects on cholesterol levels, triglyceride levels, and high density lipoprotein levels. In addition, synthetic progestins may also cause fluid retention and depression as significant side effects in contrast to natural progesterone.
A second approach has involved injectionable formulations containing progesterone or estradiol in their natural form. Obviously, daily injection of progesterone or estradiol has many disadvantages, such as pain and discomfort, necessity of maintaining sterility of the drug and hypodermic syringe, and frequent need for professional help in giving the injection.
A third approach has involved development of formulations containing estradiol or progesterone which can be orally administered. One such formulation is an orally active progesterone composition described in U.S. Pat. No. 3,284,303. The oral activity is attributed to the presence of glycerylmonostearate in the composition containing progesterone.
Another formulation is described by Rudel in U.S. Pat. No. 3,828,106. The formulation described by Rudel is said to result in enhanced oral activity of estradiol or progesterone. The oral activity is attributed to the presence of steroidal lipids into the composition. In particular, bile acids and sterols are said to be useful for enhancing the oral activity of these steroidal hormones. It is also stated by Rudel that the steroid-glyceride compositions known in the prior art, such as the ones described in U.S. Pat. 3,284,303, are not suitable due to hydrolysis of the glyceride in the intestine. Thus, it is concluded by Rudel that glyceride and triglyceride carriers, especially when used as a solvent for steroidal hormones, are to be avoided due to hydrolysis in the intestine.
In Patent No. 3,862,311, an orally active progesterone formulation is disclosed. The formulation comprises progesterone, a carrier, and a surfactant. The carrier is preferably polyethylene glycol and the surfactant is an anionic or non-ionic surfactant.
An orally active progesterone has been disclosed in Besins in U.S. Pat. No. 4,196,188. The composition described by Besins contains micronized progesterone suspended in oil for improved oral absorption. The progesterone is in the form of particles in which at least 80% of the particles are between 1-15 mm. However, Besins stresses that particle size of less than 5 mm should be avoided in order to maintain stability for longer than 3 months. Thus, the composition disclosed by Besins has a short shelf life when particle sizes of 1-5 mm are used.
An orally active form of estradiol has been developed by Mead-Johnson and sold under the name "Estrace". Estrace achieves its oral activity by administering the estradiol in the form of micronized particles.
More recently, in an application filed on Apr. 14, 1986, entitled "Pharmaceutical Composition Containing Progesterone"; Ser. No. 850,181; a composition containing miscronized progesterone in an unsaturated oil carrier was described. The composition described in the above-reference application is orally active and is said to be useful for treating pre-menstral symptoms. This composition is lacking in estradiol, which is necessary for hormonal replacement therapy in treating menopausal women. Furthermore, although the above-referenced application provides for enhanced oral activity for progesterone, it provides no information for achieving enhanced oral absorption for estradiol in combination with the progesterone.
Although it is well known to combine synthetic estrogens and progestin compounds in a single formulation, nobody has ever formulated a safe and effective orally active formulation containing estradiol and progesterone in a single dosage unit. Others have failed in meeting this objective, even though the advantages of a single pill or capsule containing both estrogen and a progestin have long been known. The most widely used oral contraceptives contain this combination of synthetic steroids. Recently, Whitehead and Colleagues (Seminars in Reproductive Endocrinology 1: 1 1983) and Magos and Colleagues (Obstet Gynecol 65: 496, 1985) reported on the use of both an estrogen (the non-human, equine, conjugated estrogen) and in a separate preparation, a synthetic progestin or natural progesterone as effective in preventing withdrawal bleeding and endometrial hypolasia in post-menopausal women.
It has also been long recognized that the equine estrogens and the other synthetic estrogens and progestins have both physiologic and non-psychologic properties. The equine estrogens contain a number of estrogen compounds (such as equilin and equilin-sulfate) which are not normally synthesized in the human. These long acting estrogens have the disadvantage of having an unknown effect on the human system.
Customary usage of estrogen and progestin for treating menopause has involved either sequential administration or continuous daily administration of separate estrogen and progestin pills or capsules. These methods of administration have been poorly tolerated for two reasons. First, the sequential administration often results in withdrawl uterine bleeding seen by the patient as a menstral period. This is not well tolerated by older women, and this bleeding often results in the discontinuation of estrogen therapy. Consequently, patients are forced to suffer with their menopausal symptoms. Additionally, discontinuation of estrogen therapy will often times result in persistant monthly withdrawal bleeding.
The disadvantage of the continuous daily preparation is that there is no single pill or capsule available except for the oral contraceptive preparations which can be taken every day in a convenient fashion and minimize the risk of withdrawal bleeding. The synthetic oral contraceptives are currently relatively contra-indicated after age 35 and are rarely prescribed after age 40, because of well known side effects of these synthetic preparations and doses.
With the advancing age of the American population, management of menopause becomes increasingly important to the practicing gynocologist. This importance will soon be amplified by the entry of the baby-boom generation into their climacteric years. In order to optimize the health of this expanding group of women, it becomes imperative that we develop menopausal hormone replacement programs that are safe, effective, and acceptable to them.
Estrogen replacement therapy is known to be effective in relieving menopausal symptoms and genital atrophy. It is useful in the prevention of osteroporosis and its sequelae. The dilemma of endometrial hyperplasia and carcinoma is, to a large extent, obviated by the addition of cyclic progestin as a part of the estrogen replacement program. However, the addition of synthetic progestin induces withdrawal bleeding, and many women find this unacceptable. Recently, continuous estrogen and progestin have been reported to eliminate uterine bleeding, yet maintain the benefits of estrogen replacement therapy. However, the safety of chronic administration of synthetic progestin has been questioned because of its adverse effects on lipids. In addition, many patients experience anonying side effects from synthetic progestin.
Therefore, there is a long felt need to provide a safe and effective hormone therapy drug for treating menopause which avoids the side effect problems associated with the synthetic estrogen and progestin drugs. In addition, effective treatment of menopause requires a formulation which can be conveniently taken every day for a long period of time and which minimizes the risk of withdrawal bleeding and adverse effects on the serum lipids. Also, there is a need for enhancing the absorption or oral activity of 17 beta-estradiol and progesterone so that higher serum levels of the active drug can be more easily and more quickly obtained.